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Saracco, G.M. Therapy of Chronic Hepatitis C. Encyclopedia. Available online: https://encyclopedia.pub/entry/20374 (accessed on 17 June 2025).
Saracco GM. Therapy of Chronic Hepatitis C. Encyclopedia. Available at: https://encyclopedia.pub/entry/20374. Accessed June 17, 2025.
Saracco, Giorgio Maria. "Therapy of Chronic Hepatitis C" Encyclopedia, https://encyclopedia.pub/entry/20374 (accessed June 17, 2025).
Saracco, G.M. (2022, March 09). Therapy of Chronic Hepatitis C. In Encyclopedia. https://encyclopedia.pub/entry/20374
Saracco, Giorgio Maria. "Therapy of Chronic Hepatitis C." Encyclopedia. Web. 09 March, 2022.
Therapy of Chronic Hepatitis C
Edit

Cure of HCV infection is defined by the achievement of the sustained virological response (SVR), i.e., undetectable HCV-RNA in the serum of patients 12 or 24 weeks after the end of antiviral treatment; this surrogate end point has been validated by observing the very low rate of post-SVR relapse and is also a surrogate marker of improved liver-related morbidity and mortality.

chronic hepatitis C direct acting antivirals extrahepatic manifestations hepatocellular carcinoma

1. Therapy of Chronic Hepatitis C

HCV affects about 71 million people worldwide [1], leading to liver cirrhosis and HCC in many cases; moreover, the infection is associated with several nonhepatic diseases with an overall mortality related to the extrahepatic complications of 580,000/year [2]. The advent of direct-acting antiviral (DAA) treatment, including RNA-dependent polymerase inhibitors (anti-NS5B), protease inhibitors (anti-NS3/4A), and anti-NS5A inhibitors, has significantly improved the therapeutic success for HCV infection, providing a simplified approach for global HCV elimination by 2030 as endorsed by the World Health Organization [3]. According to the European Association for the Study of the Liver (EASL), the aim of treatment is to cure HCV infection to prevent the complications of HCV-related liver and extrahepatic diseases, including liver necroinflammation, fibrosis, cirrhosis, decompensation of cirrhosis, HCC, and severe extrahepatic manifestations, to improve quality of life, and to prevent onward transmission of HCV [4]. Such beneficial effects have an impressive impact on the reduction in mortality, irrespective of the baseline liver fibrosis [5][6][7]. Cure of HCV infection is defined by the achievement of the sustained virological response (SVR), i.e., undetectable HCV-RNA in the serum of patients 12 or 24 weeks after the end of antiviral treatment; this surrogate end point has been validated by observing the very low rate of post-SVR relapse and is also a surrogate marker of improved liver-related morbidity and mortality [8]. Currently, there are two approved pangenotypic DAA regimen available, namely Sofosbuvir and Velpatasvir (SOF/VEL), as well as Glecaprevir and Pibrentasvir (G/P). While both regiments are effective in inducing SVR rates beyond 95% in most scenarios, only SOF/VEL is approved to treat decompensated HCV cirrhosis patients [9][10].

2. Liver Outcome

2.1. Compensated Cirrhosis

In the Interferon era, regression of fibrosis in HCV patients with cirrhosis was documented after SVR by pre- and post-therapy liver biopsies in 61% of patients [11]. It is reasonable to assume that with the advent of DAA, this histological benefit will be even more frequent. However, due to the lack of post-SVR liver biopsies, researchers have no current solid data regarding the long-term histologic outcome of cured cirrhotic patients. According to EASL, noninvasive scores and liver stiffness measurement (LSM) by transient elastography (TE) and other elastography methods are not accurate in detecting fibrosis regression after SVR and their routine use is currently not recommended [12]. It is well known that in cirrhotic patients with HCV, DAA-induced SVR decreases the risk of liver-related complications as well as all-cause mortality [13][14]. SVR is associated with a decrease in the incidence of liver-related events in the vast majority of cirrhotic patients [15][16]; in particular, DAA-induced viral clearance results in a significant reduction of incident HCC [13][17][18], while the issue regarding the recurrence rate of HCC in patients achieving SVR is still matter of debate [19][20][21].
Cirrhotic patients achieving SVR by DAAs show a progressive decrease in portal pressure during follow-up, reducing the incidence of decompensation events [15][22][23][24]. However, clinically significant portal hypertension (CSPH) may persist in a significant proportion of them [25][26][27], and several noninvasive tests (NITs) are currently used to stratify cured patients in order to better individuate patients at risk for liver decompensation [28]. According to the recent EASL guidelines [12], in successfully treated HCV-positive cirrhotic patients, LSM by TE could be helpful to refine the stratification of the residual risk of liver-related complications, even though cured cirrhotic patients should continue to be monitored for HCC by abdominal ultrasound examination ± alphafetoprotein assay every 6 months irrespective of the results of NITs. This stringent recommendation is based upon the finding that HCC is the most frequent liver-related complication after SVR [29]. The need for assessing predictive factors of HCC occurrence in order to individuate HCC surveillance has prompted many hepatologists to look for NITs, both before and after therapy, but currently no specific NITs or algorithms combining different risk factors have been officially validated [29].

2.2. Decompensated Cirrhosis

Patients with decompensated cirrhosis may benefit from antiviral treatment with DAAs, even though most clinical trials [30][31][32][33][34][35] showed a significant decrease in SVR rates among decompensated cirrhotics. However, liver function improves as confirmed by amelioration both in Child-Turcotte-Pugh (CPT) classification and Model for End- Stage Liver Disease (MELD) scores in a significant proportion of patients [36][37][38][39][40]. Whether such benefit is durable over the long-term is still matter of debate [41][42][43][44]. Moreover, such improvement is rarely found among patients with severely impaired liver function at the start of therapy [45]; for this reason, it is paramount to establish a pretreatment scoring system based upon NITs able to individuate patients in whom therapy could be futile or harmful. International guidelines [46] suggest not to treat patients with an MELD score >20 because this particular subset of patients may be delisted from liver transplantation due to transient clinical improvement while still being at risk of lethal complications (the so-called “MELD purgatory”). However, this threshold seems to be inaccurate as recent studies [44][45] showed that many patients with lower MELD scores may not obtain significant clinical benefit over the long term despite SVR.
A predictive scoring system (the BE3A scoring system) adopting five pre-therapy features (BMI, lack of encephalopathy, lack of ascites, ALT > 60 IU/L, and albuminemia > 3.5 g/dL) was recently published [47]; patients with high scores had the highest chances of achieving CPT class A, but they represented less than 5% of the considered patients. Conversely, patients with baseline low scores had less than 25% of chances of achieving CPT class A suggesting that Orthotopic Liver Transplant (OLT) would have been the best solution rather than antiviral therapy. Further studies are needed in order to validate NITs or algorithms using combinations of NITs able to define the point of no return in this particular category of patients.

2.3. Liver Transplant Setting

The advent of DAAs has revolutionized HCV treatment in the liver transplant (OLT) setting. Therapy of HCV infection pre-OLT in patients awaiting liver transplantation has two main aims: preventing liver graft infection after OLT and improving liver function before transplantation. According to the EASL guidelines [8], patients without HCC awaiting OLT with a MELD score < 18–20 should be treated prior to liver transplantation while patients with a MELD score > 18–20 should be transplanted first, and HCV infection should be addressed after OLT. Only patients with an expected waiting time on the transplant list >6 months should be treated before transplantation. Pre-OLT therapy seems to be an appropriate strategy especially in those areas where the average age of the donor exceeds 60 years [48], with a higher risk of graft dysfunction immediately after OLT [49]. Early allograft dysfunction (EAD) shows a negative clinical impact on graft and patient survival, often involving other organs such as kidneys [50]. For this reason, negativization of viremia by pre-OLT antiviral therapy should be a priority in order to prevent graft infection at reperfusion and to reduce EAD incidence [51].
However, unpredictable waiting time, antiviral therapy duration, risk of patient death on the list, and higher rates of SVR in transplant recipients compared with decompensated cirrhotic patients induce clinicians to treat infection after OLT. In fact, treatment following liver transplantation has greatly ameliorated post-OLT survival [52][53], with an overall SVR rate > 95%. Thanks to recent studies [54][55], international recommendations [8] regarding this hot issue were finally drawn, suggesting pre-OLT therapy for patients without HCC with a MELD score ≤ 20, while DAAs after OLT are cost-effective in patients with a MELD score > 20.

2.4. Extrahepatic Manifestations Outcome

A causal relationship between HCV infection and extrahepatic manifestations (EM) (in particular, cryoglobulinemic syndrome, Non-Hodgkin’s Lymphoma (NHL), diabetes mellitus (DM), cardiovascular, neurological, and kidney diseases) was proven [56] and current guidelines [4][57] strongly recommend DAA therapy in HCV-positive patients with clinically significant extrahepatic manifestations. The advent of such treatment has significantly decreased the overall prevalence of HCV-related EM [56] even though the conclusive amount of the beneficial effects has not yet been completely assessed due to the short follow-up and the controversial results reported so far.

2.5. Mixed Cryoglobulinemia

Mixed cryoglobulinemia (MC) is a B-cell lymphoproliferative disorder and consists of polyclonal IgG with monoclonal or polyclonal IgM and rheumatoid factor activity which precipitate when the temperature is below 37 °C, determining a small-vessel systemic vasculitis [58]. Symptoms of MC vasculitis are also known as MC syndrome, which is characterized by palpable purpura, weakness, and arthralgias and by several organs and tissue involvement such as skin, kidney, nervous, cardiovascular, and digestive systems [59]. MC is present in about 40–60% of HCV-positive patients and up to 30% of them show symptomatic cryoglobulinemic vasculitis (CV) [60][61][62]; 5–10% show an evolution to NHL [60][63][64] with a reduced life expectancy [58][65].
The introduction of DAAs has led to a complete or partial remission of the CV-related manifestations in the vast majority of patients with only a minority of nonresponders/relapsers [66][67][68][69][70][71][72][73][74][75][76]. However, long-term complete eradication of MC is observed in only 29–66% of patients [56], reflecting a B-cell clonal expansion persistence [77][78][79]. From a clinical point of view, this persistence is associated to the maintenance or recurrence of CV-related symptoms in a nonnegligible minority of patients, in particular among those with renal and/or neurological involvement [70][71][72][73][74][75][76].
When compared with the Interferon (IFN) era, DAA-induced clinical results regarding CV seem to be less definitive, suggesting that IFN could be better than DAAs on clinic-immunological outcomes due to its antiproliferative and immunologic activity. For this reason and due to the risk of NHL occurrence, long-term follow-up of patients with MC achieving SVR is mandatory.

2.6. B-Cell Non Hodgkin’s Lymphoma

NHL comprises different lymphoproliferative disorders, but the link between HCV and haematological neoplasias was only proven for specific B-cell origin malignancies (B-NHL) [80].
B-NHLs most frequently associated with HCV are the marginal zone lymphoma, lymphoplasmacytic lymphoma, and diffuse large B-cell lymphoma [81]. The pathophysiology of such correlation is still matter of debate, but it is likely that continuous and sustained stimulation of lymphocyte receptors by viral antigen, viral replication in B cells, amd genetic alterations play a significant role in the lymphomagenesis [82]. The prevalence of HCV-associated B-NHL is variable, ranging from 20% in Italy to 6% in Europe (with the exclusion of Italy) [56]. Several reports have shown the regression of HCV-related indolent B-NHL with IFN-free antiviral therapy with very high rates of progression-free survival at 1 year [83][84][85][86][87][88][89]. These impressive results associated to the elevated tolerability and safety of DAAs have prompted many hepatologists to start antiviral treatment prior to administration of chemotherapy also in patients with aggressive B-NHL in order to neutralize B-NHL trigger and decrease the risk of relapse.

2.7. Neurologic Manifestations

Neurologic and neuropsychiatric manifestations may occur in about 15–45% of HCV-positive patients [90]; peripheral neuropathy (PN) characterized by sensory loss and motor weakness [91] is mainly due to CV which induces a neural ischemic damage by occluding the epineural arterioles and small vessels. In contrast to PN, symptoms of central nervous system impairment (anxiety, depression, fatigue, attention and memory deficits, sleep disturbances, and confusion) are rarely due to CV; a direct neurotoxic effect has been hypothesized thanks to the finding of brain neuro-invasion by HCV and intrathecal replication [92][93]. Studies published so far [69][72][74][78][94][95][96][97][98] on the impact of DAA-based treatment on neurologic disorders have shown a significant reduction of neuropathic pain, even though PN demonstrated a lower clinical response [90] compared to cutaneous and articular manifestations (30–70% vs. 75–100%). A beneficial effect on neuropsychiatric and cognitive affections related to HCV infection was also found [99][100], with the improvement of fatigue, sleep disturbances, vitality, mental component summary, general health, and in the activity of cerebral cortex profiles.

2.8. Chronic Kidney Disease

HCV-positive patients have a higher risk of chronic kidney disease (CKD) than uninfected patients [101][102][103], and various mechanisms have been reported to explain this difference; the most frequent is a membranoproliferative damage induced by CV [56][104] but CV-free membranoproliferative glomerulonephritis, membranous nephropathy, and tubulointerstitial injury are also described [105][106]. Once it is established that the kidney is a relevant target of the extrahepatic activity of HCV, it is reasonable to assume that achievement of SVR may reduce the incidence of “de novo” kidney diseases and improve concomitant nephropaties. All approved DAAs can be used in patients with mild-to-moderate renal impairment [107], and recently the exclusion of sofosbuvir-based therapies in patients with severe renal impairment has been removed [108]. The great majority of studies published so far [109][110][111][112][113][114][115][116] have shown that DAAs are effective in lowering the risk of kidney disease in HCV-positive patients and in stabilizing/improving renal function in patients with CKD, even though the long-term impact on kidney survival is still largely unknown [56].

2.9. Cardiovascular Diseases

There is robust evidence that HCV infection is associated with cardiovascular diseases (CVD) [117][118][119], exerting its detrimental effect through direct (inducing a proinflammatory and profibrogenic environment) and indirect (determining metabolic co-morbidities such as insulin resistance (IR) and DM) mechanisms [120].
The advent of DAAs has led to a significant reduction of the risk of cardiovascular events [121][122][123][124], and this strong clinical impact is still maintained even when potential confounders such as liver fibrosis are considered [125][126]. This effect is probably due to the decrement in atherosclerosis as reported by Italian authors in [127][128][129].
The SVR induced by DAAs on CVD is still a matter of debate; larger prospective studies with longer follow-ups are needed before drawing definite conclusions regarding the long term benefits of viral clearance.

2.10. Diabetes Mellitus

Several reviews and meta-analyses [130][131][132] have shown a higher incidence and prevalence of DM in patients with HCV than in controls. According to some authors [133][134], the virus can interfere with insulin signaling, eventually inducing alterations in glucose homeostasis. However, recent data suggested a direct role of HCV [135] by inducing death of pancreatic beta cells and upregulating several hepatokines known to cause insulin resistance. Achieving SVR by DAAs is associated with a reduced incidence of DM and a significant improvement in glycemic control among diabetic patients [56][136][137][138][139][140], [141][142][143][144][145][146][147][148][149][150]). Moreover, this beneficial effect seems to have a clinical impact on DM-related complications [124].
Howeverd the influence of DAA-induced SVR on the long-term outcome of DM in diabetics remains largely unknown; few studies with long-term follow-up addressing this issue have been published, and they present conflicting results [145][150]. To explain this discrepancy, it is important to note that the glycometabolic control may be affected by viral clearance and genetic and lifestyle-related factors, such as dietary habits, physical activity, and therapeutic adherence, which are prone to change over the long term.
In conclusion, with the introduction of DAAs, the great majority of treated patients definitively cleared the virus and achieved a permanent recovery, with a significant improvement in liver-related outcomes and extra-hepatic manifestations. However, unsolved issues remain, including the role of DAAs in patients with decompensated advanced liver disease, the management of patients not responding or relapsing after treatment with DAAs, and the persisting risk of HCC in cirrhotics after achieving SVR. Moreover, due to the limited worldwide access to healthcare, the majority of patients remain untreated and undiagnosed, and will develop liver complications in the future. For this reason, international organizations and high-income countries should help low-income countries to prioritize screening policies and access to DAA treatment.
This entry is adapted from 10.3390/biomedicines10030534

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